Genetic Risk for Granulomatous Interstitial Lung Disease

肉芽肿性间质性肺病的遗传风险

基本信息

批准号：
8506183
负责人：
Tasha E. Fingerlin
金额：
$ 67.36万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8506183
关键词：
Affect African American Age Alleles Antigens Cessation of life Characteristics Chronic berylliosis Control Groups Controlled Study Data Development Disease Environmental Exposure Environmental Risk Factor Ethnic group Female Fibrosis Gender Genes Genetic Genetic Determinism Genetic Predisposition to Disease Genetic Risk Genome Goals Granulomatous HLA Antigens Immune Immune response Impairment Individual Inflammation Interstitial Lung Diseases Lead Learning Lesion Long-Term Effects Lung Lung diseases Major Histocompatibility Complex Maps Mediating Modification Morbidity - disease rate Mutation Not Hispanic or Latino Organ Other Genetics Phenotype Play Population Predisposition Prevalence Prevention Prevention strategy Process Pulmonary Sarcoidosis Qualifying Race Research Personnel Research Project Grants Resolution Respiratory Failure Risk Risk Factors Role SNP genotyping Sampling Sampling Studies Sarcoidosis Severities Severity of illness Smoking Smoking History Spirometry Staging Stimulus Subgroup Testing United States Variant base case control cigarette smoking disorder risk experience follow-up genetic risk factor genetic variant genome wide association study genome-wide male mortality public health relevance risk variant screening treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to identify genetic risk factors for lung-involved sarcoidosis, a granulomatous interstitial lung disease (gILD). Lung-involved sarcoidosis results from an aberrant adaptive immune response to unknown antigenic stimuli. The prevalence of sarcoidosis is estimated to be between 10 and 35 per 100,000 in the United States, affecting people of all races, both genders and all ages. In some individuals, the immune response resolves with no long-term effects while in others there is severe lung impairment. We do not understand the mechanisms of granulomatous disease initiation nor why disease resolves in some individuals but progresses to severe disease, often resulting in death, in others. The mortality rate of sarcoidosis is increasing for reasons we also don't understand. Both genetic and environmental factors are important for determining sarcoidosis risk and the impact of environmental exposures on disease risk and severity likely differs depending on genetic factors. There is good evidence for the importance of immune-related genetic variants in sarcoidosis, although the specific immune-related variants and other genetic determinants of risk remain largely unidentified. Cigarette smoking is protective for sarcoidosis, but protection differs greatly among those with similar smoking histories. The central hypothesis of this proposal is that genetic variants in the major histocompatibility complex (MHC) play a primary role in the initiation of sarcoidosis by modulating antigen stimulation and that these variants, in addition to others, drive the initiation and perpetuation of granulomatous inflammation and ultimately disease severity. This project will identify genetic variants associated with lung- involved sarcoidosis by comparing cases with sarcoidosis to controls using both targeted examination of the MHC and agnostic screening of the genome via the HumanOmni2.5 BeadChip. To do so, this project will examine the most powerful discovery sample studied to date, prioritize variants based on expression findings from other projects and replicate our findings in independent samples. This project will also characterize the potential etiologic roles of reproducibly associated sarcoidosis risk variants by examining important smoking exposure and disease severity subgroups to determine whether disease risk depends on smoking history and/or whether these variants are associated with severity of lung involvement. The results of this study should provide important genes or regions for follow-up fine-mapping and functional studies that should ultimately provide better prevention and treatment targets for development.

描述（由申请人提供）：该项目的目的是确定肺涉及结节病的遗传危险因素，肺部肺部肺部疾病（GILD）。肺涉及的结节病是由对未知抗原刺激的异常适应性免疫反应引起的。在美国，结节病的患病率估计在每100,000人中10至35之间，影响了各个种族的人，包括性别和所有年龄段的人。在某些人中，免疫反应没有长期影响，而在另一些人则存在严重的肺部损害。我们不了解肉芽肿性疾病起步的机制，也不了解为什么疾病在某些人中得到解决，而是发展为严重疾病，通常导致死亡。由于我们也不了解的原因，结节病的死亡率正在增加。遗传和环境因素对于确定结节症风险以及环境暴露对疾病风险和严重程度的影响很重要，这取决于遗传因素。有充分的证据表明，尽管特定的与免疫相关的变体和其他风险的其他遗传决定因素在很大程度上不明显。吸烟对结节病具有保护作用，但是在具有相似吸烟史的人群中，保护却大不相同。该提议的中心假设是，主要组织相容性复合物（MHC）中的遗传变异在结节病的开始中起着主要作用，通过调节抗原刺激，并且这些变体在除其他外，还可以推动肉芽肿性炎症和最终疾病严重程度的启动和永久性。该项目将通过比较结节病的病例与对照组，同时使用Handomni2.5 Beadchip进行基因组的靶向检查，从而鉴定与肺部相关的遗传变异。为此，该项目将检查迄今为止研究的最强大的发现样本，根据其他项目的表达发现优先考虑变体，并在独立样本中复制我们的发现。该项目还将通过检查重要的吸烟暴露和疾病严重性亚组来确定疾病风险是否取决于吸烟病史和/或这些变体是否与肺部受累严重性相关，从而表征可重复相关的结节病风险变异的潜在病因作用。这项研究的结果应提供重要的基因或区域，以进行随访精细映射和功能研究，最终应提供更好的预防和治疗目标的开发目标。